title: The branched-chain aminotransferase proteins: novel redox chaperones for protein disulfide isomerase--implications in Alzheimer's disease.
abstract: OBJECTIVE
  The human branched-chain aminotransferase proteins (hBCATm and hBCATc) are regulated through oxidation and S-nitrosation. However, it remains unknown whether they share common redox characteristics to enzymes such as protein disulfide isomerase (PDI) in terms of regulating cellular repair and protein misfolding.
  
  
  RESULTS
  Here, similar to PDI, the hBCAT proteins showed dithiol-disulfide isomerase activity that was mediated through an S-glutathionylated mechanism. Site-directed mutagenesis of the active thiols of the CXXC motif demonstrates that they are fundamental to optimal protein folding. Far Western analysis indicated that both hBCAT proteins can associate with PDI. Co-immunoprecipitation studies demonstrated that hBCATm directly binds to PDI in IMR-32 cells and the human brain. Electron and confocal microscopy validated the expression of PDI in mitochondria (using Mia40 as a mitochondrial control), where both PDI and Mia40 were found to be co-localized with hBCATm. Under conditions of oxidative stress, this interaction is decreased, suggesting that the proposed chaperone role for hBCATm may be perturbed. Moreover, immunohistochemistry studies show that PDI and hBCAT are expressed in the same neuronal and endothelial cells of the vasculature of the human brain, supporting a physiological role for this binding.
  
  
  METHODS
  This study identifies a novel redox role for hBCAT and confirms that hBCATm differentially binds to PDI under cellular stress.
  
  
  CONCLUSIONS
  These studies indicate that hBCAT may play a role in the stress response of the cell as a novel redox chaperone, which, if compromised, may result in protein misfolding, creating aggregates as a key feature in neurodegenerative conditions such as Alzheimer's disease.
authors.affiliation: 1 Faculty of Health and Life Sciences, University of the West of England , Coldharbor Lane, Bristol, United Kingdom .
authors.forename: Maya
authors.initials: M
authors.lastname: El Hindy
authors.forename: Mohammed
authors.initials: M
authors.lastname: Hezwani
authors.forename: David
authors.initials: D
authors.lastname: Corry
authors.forename: Jonathon
authors.initials: J
authors.lastname: Hull
authors.forename: Farah
authors.initials: F
authors.lastname: El Amraoui
authors.forename: Matthew
authors.initials: M
authors.lastname: Harris
authors.forename: Christopher
authors.initials: C
authors.lastname: Lee
authors.forename: Thomas
authors.initials: T
authors.lastname: Forshaw
authors.forename: Andrew
authors.initials: A
authors.lastname: Wilson
authors.forename: Abbe
authors.initials: A
authors.lastname: Mansbridge
authors.forename: Martin
authors.initials: M
authors.lastname: Hassler
authors.forename: Vinood B
authors.initials: VB
authors.lastname: Patel
authors.forename: Patrick Gavin
authors.initials: PG
authors.lastname: Kehoe
authors.forename: Seth
authors.initials: S
authors.lastname: Love
authors.forename: Myra Elizabeth
authors.initials: ME
authors.lastname: Conway
mesh_terms: D000544:Alzheimer Disease / Q000201:enzymology* / Q000378:metabolism / Q000473:pathology; D002460:Cell Line; D006801:Humans; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D019704:Protein Disulfide-Isomerases / Q000378:metabolism*; D000637:Transaminases / Q000378:metabolism*
chemical_list: D000637:Transaminases; D019704:Protein Disulfide-Isomerases